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Östlund Farrants, Ann-KristinORCID iD iconorcid.org/0000-0001-9225-3264
Alternative names
Publications (10 of 38) Show all publications
Lasaviciute, G., Barz, M., van Der Heiden, M., Arasa, C., Tariq, K., Quin, J., . . . Sverremark-Ekström, E. (2022). Gut commensal Limosilactobacillus reuteri induces atypical memory-like phenotype in human dendritic cells in vitro. Gut microbes, 14(1), Article ID 2045046.
Open this publication in new window or tab >>Gut commensal Limosilactobacillus reuteri induces atypical memory-like phenotype in human dendritic cells in vitro
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2022 (English)In: Gut microbes, ISSN 1949-0976, E-ISSN 1949-0984, Vol. 14, no 1, article id 2045046Article in journal (Refereed) Published
Abstract [en]

Memory-like responses in innate immune cells confer nonspecific protection against secondary exposures. A number of microbial agents have been found to induce enhanced or diminished recall responses in innate cells, however, studies investigating the ability of probiotic bacteria to trigger such effects are lacking. Here, we show that priming of human monocytes with a secretome from the gut probiotic bacterium Limosilactobacillus (L.) reuteri induces a mixed secondary response phenotype in monocyte-derived dendritic cells (mo-DCs), with a strong IL-6 and IL-1β response but low TNFα, IL-23 and IL-27 secretion. Instead, blood DC priming with L. reuteri-secretome resembles a tolerant state upon secondary exposure. A similar pattern was found in conventional and gut-like (retinoic acid exposed) DCs, although retinoic acid hampered TNFα and IL-6 production and enrichment of histone modifications in L. reuteri-secretome primed mo-DC cultures. Further, we show that the memory-like phenotype of mo-DCs, induced by priming stimuli, is important for subsequent T helper (Th) cell differentiation pathways and might determine the inflammatory nature of Th cells. We also show enhanced recall responses characterized by robust inflammatory cytokines and lactate production in the gut-like mo-DCs derived from β-glucan primed monocytes. Such responses were accompanied with enriched histone modifications at the promoter of genes associated with a trained phenotype in myeloid cells. Altogether, we demonstrate that a gut commensal-derived secretome prompts recall responses in human DCs which differ from that induced by classical training agents such as β-glucan. Our results could be beneficial for future therapeutic interventions where T cell responses are needed to be modulated.

Keywords
Limosilactobacillus reuteri, dendritic cells, T helper cells, innate immune memory, epigenetics
National Category
Biological Sciences Immunology in the medical area
Identifiers
urn:nbn:se:su:diva-203478 (URN)10.1080/19490976.2022.2045046 (DOI)000765991300001 ()35258405 (PubMedID)2-s2.0-85125981330 (Scopus ID)
Available from: 2022-04-05 Created: 2022-04-05 Last updated: 2022-05-09Bibliographically approved
Gañez-Zapater, A., Mackowiak, S. D., Guo, Y., Tarbier, M., Jordán-Pla, A., Friedländer, M. R., . . . Östlund Farrants, A.-K. (2022). The SWI/SNF subunit BRG1 affects alternative splicing by changing RNA binding factor interactions with nascent RNA. Molecular Genetics and Genomics, 297(2), 463-484
Open this publication in new window or tab >>The SWI/SNF subunit BRG1 affects alternative splicing by changing RNA binding factor interactions with nascent RNA
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2022 (English)In: Molecular Genetics and Genomics, ISSN 1617-4615, E-ISSN 1617-4623, Vol. 297, no 2, p. 463-484Article in journal (Refereed) Published
Abstract [en]

BRG1 and BRM are ATPase core subunits of the human SWI/SNF chromatin remodelling complexes mainly associated with transcriptional initiation. They also have a role in alternative splicing, which has been shown for BRM-containing SWI/SNF complexes at a few genes. Here, we have identified a subset of genes which harbour alternative exons that are affected by SWI/SNF ATPases by expressing the ATPases BRG1 and BRM in C33A cells, a BRG1- and BRM-deficient cell line, and analysed the effect on splicing by RNA sequencing. BRG1- and BRM-affected sub-sets of genes favouring both exon inclusion and exon skipping, with only a minor overlap between the ATPase. Some of the changes in alternative splicing induced by BRG1 and BRM expression did not require the ATPase activity. The BRG1-ATPase independent included exons displayed an exon signature of a high GC content. By investigating three genes with exons affected by the BRG-ATPase-deficient variant, we show that these exons accumulated phosphorylated RNA pol II CTD, both serine 2 and serine 5 phosphorylation, without an enrichment of the RNA polymerase II. The ATPases were recruited to the alternative exons, together with both core and signature subunits of SWI/SNF complexes, and promoted the binding of RNA binding factors to chromatin and RNA at the alternative exons. The interaction with the nascent RNP, however, did not reflect the association to chromatin. The hnRNPL, hnRNPU and SAM68 proteins associated with chromatin in cells expressing BRG1 and BRM wild type, but the binding of hnRNPU to the nascent RNP was excluded. This suggests that SWI/SNF can regulate alternative splicing by interacting with splicing-RNA binding factor and influence their binding to the nascent pre-mRNA particle.

Keywords
mRNA alternative splicing, Exon GC content, Chromatin remodelling, SWI/SNF, BRGG1, hnRNPL, hnRNPU, SAM68
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-202889 (URN)10.1007/s00438-022-01863-9 (DOI)000758072300001 ()35187582 (PubMedID)2-s2.0-85124836307 (Scopus ID)
Available from: 2022-03-18 Created: 2022-03-18 Last updated: 2022-03-30Bibliographically approved
Tariq, K. & Östlund Farrants, A.-K. (2021). Antagonising Chromatin Remodelling Activities in the Regulation of Mammalian Ribosomal Transcription. Genes, 12(7), Article ID 961.
Open this publication in new window or tab >>Antagonising Chromatin Remodelling Activities in the Regulation of Mammalian Ribosomal Transcription
2021 (English)In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 12, no 7, article id 961Article, review/survey (Refereed) Published
Abstract [en]

Ribosomal transcription constitutes the major energy consuming process in cells and is regulated in response to proliferation, differentiation and metabolic conditions by several signalling pathways. These act on the transcription machinery but also on chromatin factors and ncRNA. The many ribosomal gene repeats are organised in a number of different chromatin states; active, poised, pseudosilent and repressed gene repeats. Some of these chromatin states are unique to the 47rRNA gene repeat and do not occur at other locations in the genome, such as the active state organised with the HMG protein UBF whereas other chromatin state are nucleosomal, harbouring both active and inactive histone marks. The number of repeats in a certain state varies on developmental stage and cell type; embryonic cells have more rRNA gene repeats organised in an open chromatin state, which is replaced by heterochromatin during differentiation, establishing different states depending on cell type. The 47S rRNA gene transcription is regulated in different ways depending on stimulus and chromatin state of individual gene repeats. This review will discuss the present knowledge about factors involved, such as chromatin remodelling factors NuRD, NoRC, CSB, B-WICH, histone modifying enzymes and histone chaperones, in altering gene expression and switching chromatin states in proliferation, differentiation, metabolic changes and stress responses.

Keywords
rRNA gene repeats, chromatin states, NuRD, B-WICH, NoRC, histone modifications, non-coding RNA
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-197360 (URN)10.3390/genes12070961 (DOI)000676577200001 ()34202617 (PubMedID)
Available from: 2021-09-30 Created: 2021-09-30 Last updated: 2022-02-25Bibliographically approved
Rolicka, A., Guo, Y., Gañez Zapater, A., Tariq, K., Quin, J., Vintermist, A., . . . Östlund Farrants, A. (2020). The chromatin‐remodeling complexes B‐WICH and NuRD regulate ribosomal transcription in response to glucose. The FASEB Journal, 34(8), 10818-10834
Open this publication in new window or tab >>The chromatin‐remodeling complexes B‐WICH and NuRD regulate ribosomal transcription in response to glucose
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2020 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 34, no 8, p. 10818-10834Article in journal (Refereed) Published
Abstract [en]

Regulation of ribosomal transcription is under tight control from environmental stimuli, and this control involves changes in the chromatin structure. The underlying mechanism of how chromatin changes in response to nutrient and energy supply in the cell is still unclear. The chromatin‐remodeling complex B‐WICH is involved in activating the ribosomal transcription, and we show here that knock down of the B‐WICH component WSTF results in cells that do not respond to glucose. The promoter is less accessible, and RNA pol I and its transcription factors SL1/TIF‐1B and RRN3/TIF‐1A, as well as the proto‐oncogene c‐MYC and the activating deacetylase SIRT7 do not bind upon glucose stimulation. In contrast, the repressive chromatin state that forms after glucose deprivation is reversible, and RNA pol I factors are recruited. WSTF knock down results in an accumulation of the ATPase CHD4, a component of the NuRD chromatin remodeling complex, which is responsible for establishing a repressive poised state at the promoter. The TTF‐1, which binds and affect the binding of the chromatin complexes, is important to control the association of activating chromatin component UBF. We suggest that B‐WICH is required to allow for a shift to an active chromatin state upon environmental stimulation, by counteracting the repressive state induced by the NuRD complex.

Keywords
CHD4, chromatin remodeling, c-MYC, ribosomal genes, TTF-1, WSTF
National Category
Cell Biology
Identifiers
urn:nbn:se:su:diva-184041 (URN)10.1096/fj.202000411R (DOI)000546063500001 ()
Available from: 2020-08-12 Created: 2020-08-12 Last updated: 2022-02-26Bibliographically approved
Troye-Blomberg, M., Arama, C., Quin, J., Bujila, I. & Östlund Farrants, A.-K. (2020). What will studies of Fulani individuals naturally exposed to malaria teach us about protective immunity to malaria?. Scandinavian Journal of Immunology, 92(4), Article ID e12932.
Open this publication in new window or tab >>What will studies of Fulani individuals naturally exposed to malaria teach us about protective immunity to malaria?
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2020 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 92, no 4, article id e12932Article, review/survey (Refereed) Published
Abstract [en]

There are an estimated over 200 million yearly cases of malaria worldwide. Despite concerted international effort to combat the disease, it still causes approximately half a million deaths every year, the majority of which are young children with Plasmodium falciparum infection in sub-Saharan Africa. Successes are largely attributed to malaria prevention strategies, such as insecticide-treated mosquito nets and indoor spraying, as well as improved access to existing treatments. One important hurdle to new approaches for the treatment and prevention of malaria is our limited understanding of the biology of Plasmodium infection and its complex interaction with the immune system of its human host. Therefore, the elimination of malaria in Africa not only relies on existing tools to reduce malaria burden, but also requires fundamental research to develop innovative approaches. Here, we summarize our discoveries from investigations of ethnic groups of West Africa who have different susceptibility to malaria.

Keywords
B cells, dendritic cells, inflammation, macrophages, monocytes, parasitic, T cells
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:su:diva-187673 (URN)10.1111/sji.12932 (DOI)000576528300014 ()32652609 (PubMedID)
Available from: 2020-12-21 Created: 2020-12-21 Last updated: 2022-03-23Bibliographically approved
Prakash, V., Carson, B. B., Feenstra, J. M., Dass, R. A., Sekyrova, P., Hoshino, A., . . . Vincent, C. T. (2019). Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease. Nature Communications, 10, Article ID 2110.
Open this publication in new window or tab >>Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease
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2019 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 10, article id 2110Article in journal (Refereed) Published
Abstract [en]

Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ER alpha) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-169248 (URN)10.1038/s41467-019-10100-8 (DOI)000467371400008 ()31068593 (PubMedID)
Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2023-03-28Bibliographically approved
Xie, X., Almuzzaini, B., Drou, N., Kremb, S., Yousif, A., Östlund Farrants, A.-K., . . . Percipalle, P. (2018). beta-Actin-dependent global chromatin organization and gene expression programs control cellular identity. The FASEB Journal, 32(3), 1296-1314
Open this publication in new window or tab >>beta-Actin-dependent global chromatin organization and gene expression programs control cellular identity
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2018 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 32, no 3, p. 1296-1314Article in journal (Refereed) Published
Abstract [en]

During differentiation and development, cell fate and identity are established by waves of genetic reprogramming. Although the mechanisms are largely unknown, during these events, dynamic chromatin reorganization is likely to ensure that multiple genes involved in the same cellular functions are coregulated, depending on the nuclear environment. In this study, using high-content screening of embryonic fibroblasts from a beta-actin knockout (KO) mouse, we found major chromatin rearrangements and changes in histone modifications, such as methylated histone (H)3-lysine-(K)9. Genome-wide H3K9 trimethylation-(Me)3 landscape changes correlate with gene up-and down-regulation in beta-actin KO cells. Mechanistically, we found loss of chromatin association by the Brahma-related gene (Brg)/Brahma-associated factor (BAF) chromatin remodeling complex subunit Brg1 in the absence of beta-actin. This actin-dependent chromatin reorganization was concomitant with the up-regulation of sets of genes involved in angiogenesis, cytoskeletal organization, andmyofibroblast features in beta-actin KO cells. Some of these genes and phenotypes were gained in a beta-actin dose-dependent manner. Moreover, reintroducing a nuclear localization signal-containing beta-actin in the knockout cells affected nuclear features and gene expression. Our results suggest that, by affecting the genome-wide organization of heterochromatin through the chromatin-binding activity of the BAF complex, beta-actin plays an essential role in the determination of gene expression programs and cellular identity.

Keywords
chromatin, epigenetics, genomic reprogramming, genome-wide analysis, nuclear actin
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-155993 (URN)10.1096/fj.201700753R (DOI)000427246000015 ()29101221 (PubMedID)
Available from: 2018-05-11 Created: 2018-05-11 Last updated: 2022-02-26Bibliographically approved
Arama, C., Quin, J. E., Kouriba, B., Östlund Farrants, A.-K., Troye-Blomberg, M. & Doumbo, O. K. (2018). Epigenetics and Malaria Susceptibility/Protection: A Missing Piece of the Puzzle. Frontiers in Immunology, 9, Article ID 1733.
Open this publication in new window or tab >>Epigenetics and Malaria Susceptibility/Protection: A Missing Piece of the Puzzle
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2018 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 9, article id 1733Article, review/survey (Refereed) Published
Abstract [en]

A better understanding of stable changes in regulation of gene expression that result from epigenetic events is of great relevance in the development of strategies to prevent and treat infectious diseases. Histone modification and DNA methylation are key epigenetic mechanisms that can be regarded as marks, which ensure an accurate transmission of the chromatin states and gene expression profiles over generations of cells. There is an increasing list of these modifications, and the complexity of their action is just beginning to be understood. It is clear that the epigenetic landscape plays a fundamental role in most biological processes that involve the manipulation and expression of DNA. Although the molecular mechanism of gene regulation is relatively well understood, the hierarchical order of events and dependencies that lead to protection against infection remain largely unknown. In this review, we propose that host epigenetics is an essential, though relatively under studied, factor in the protection or susceptibility to malaria.

Keywords
epigenetic, immunity, malaria, falciparum, protection, susceptibility
National Category
Biological Sciences Microbiology in the medical area
Identifiers
urn:nbn:se:su:diva-158903 (URN)10.3389/fimmu.2018.01733 (DOI)000440720400001 ()
Available from: 2018-08-20 Created: 2018-08-20 Last updated: 2024-01-17Bibliographically approved
Yu, S., Jordán-Pla, A., Gañez-Zapater, A., Jain, S., Rolicka, A., Östlund-Farrants, A.-K. & Visa, N. (2018). SWI/SNF interacts with cleavage and polyadenylation factors and facilitates pre-mRNA 3' end processing. Nucleic Acids Research, 46(16), 8557-8573
Open this publication in new window or tab >>SWI/SNF interacts with cleavage and polyadenylation factors and facilitates pre-mRNA 3' end processing
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2018 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 16, p. 8557-8573Article in journal (Refereed) Published
Abstract [en]

SWI/SNF complexes associate with genes and regulate transcription by altering the chromatin at the promoter. It has recently been shown that these complexes play a role in pre-mRNA processing by associating at alternative splice sites. Here, we show that SWI/SNF complexes are involved also in pre-mRNA 3′ end maturation by facilitating 3′ end cleavage of specific pre-mRNAs. Comparative proteomics show that SWI/SNF ATPases interact physically with subunits of the cleavage and polyadenylation complexes in fly and human cells. In Drosophila melanogaster, the SWI/SNF ATPase Brahma (dBRM) interacts with the CPSF6 subunit of cleavage factor I. We have investigated the function of dBRM in 3′ end formation in S2 cells by RNA interference, single-gene analysis and RNA sequencing. Our data show that dBRM facilitates pre-mRNA cleavage in two different ways: by promoting the association of CPSF6 to the cleavage region and by stabilizing positioned nucleosomes downstream of the cleavage site. These findings show that SWI/SNF complexes play a role also in the cleavage of specific pre-mRNAs in animal cells.

National Category
Cell and Molecular Biology
Research subject
Cell Biology
Identifiers
urn:nbn:se:su:diva-161378 (URN)10.1093/nar/gky438 (DOI)000450950500043 ()
Available from: 2018-10-23 Created: 2018-10-23 Last updated: 2022-03-23Bibliographically approved
Jordán-Pla, A., Yu, S., Waldholm, J., Källman, T., Östlund Farrants, A.-K. & Visa, N. (2018). SWI/SNF regulates half of its targets without the need of ATP-driven nucleosome remodeling by Brahma. BMC Genomics, 19, Article ID 367.
Open this publication in new window or tab >>SWI/SNF regulates half of its targets without the need of ATP-driven nucleosome remodeling by Brahma
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2018 (English)In: BMC Genomics, E-ISSN 1471-2164, Vol. 19, article id 367Article in journal (Refereed) Published
Abstract [en]

Background: Brahma (BRM) is the only catalytic subunit of the SVVI/SNF chromatin-remodeling complex of Drosophila melanogaster. The function of SWI/SNF in transcription has long been attributed to its ability to remodel nucleosomes, which requires the ATPase activity of BRM. However, recent studies have provided evidence for a non-catalytic function of BRM in the transcriptional regulation of a few specific genes.

Results: Here we have used RNA-seq and ChIP-seq to identify the BRM target genes in 52 cells, and we have used a catalytically inactive BRM mutant (K804R) that is unable to hydrolyze ATP to investigate the magnitude of the non-catalytic function of BRM in transcription regulation. We show that 49% of the BRM target genes in 52 cells are regulated through mechanisms that do not require BRM to have an ATPase activity. We also show that the catalytic and non-catalytic mechanisms of SVVI/SNF regulation operate on two subsets of genes that differ in promoter architecture and are linked to different biological processes.

Conclusions: This study shows that the non-catalytic role of SWI/SNF in transcription regulation is far more prevalent than previously anticipated and that the genes that are regulated by SVVI/SNF through ATPase-dependent and ATPase-independent mechanisms have specialized roles in different cellular and developmental processes.

Keywords
SWI/SNF, Gene expression, Transcription regulation, Drosophila melanogaster
National Category
Environmental Biotechnology Biological Sciences
Identifiers
urn:nbn:se:su:diva-157741 (URN)10.1186/s12864-018-4746-2 (DOI)000432702400002 ()29776334 (PubMedID)
Available from: 2018-08-03 Created: 2018-08-03 Last updated: 2024-01-17Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-9225-3264

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